Excitatory neuron–specific SHP2-ERK signaling network regulates synaptic plasticity and memory

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Science Signaling  05 Mar 2019:
Vol. 12, Issue 571, eaau5755
DOI: 10.1126/scisignal.aau5755

Cell type–specific RASopathy

The neurodevelopmental disorder Noonan syndrome is often caused by activating mutations in the phosphatase SHP2 that enhance RAS signaling. However, SHP2 is present in multiple neuron types as well as glia; thus, where the mutant protein has its pathological effects is unclear. Ryu et al. examined one NS-associated SHP2 mutation in isolated cell types from mice and determined that its presence in only excitatory neurons resulted in electrophysiological and cognitive effects. This was because certain adaptor proteins that interact with SHP2 to mediate RAS signaling are abundant in excitatory but not inhibitory neurons. These findings reveal that cell type–specific variations within the RAS signaling network underlie the phenotypes of NS and possibly other “RASopathies”.


Mutations in RAS signaling pathway components cause diverse neurodevelopmental disorders, collectively called RASopathies. Previous studies have suggested that dysregulation in RAS–extracellular signal–regulated kinase (ERK) activation is restricted to distinct cell types in different RASopathies. Some cases of Noonan syndrome (NS) are associated with gain-of-function mutations in the phosphatase SHP2 (encoded by PTPN11); however, SHP2 is abundant in multiple cell types, so it is unclear which cell type(s) contribute to NS phenotypes. Here, we found that expressing the NS-associated mutant SHP2D61G in excitatory, but not inhibitory, hippocampal neurons increased ERK signaling and impaired both long-term potentiation (LTP) and spatial memory in mice, although endogenous SHP2 was expressed in both neuronal types. Transcriptomic analyses revealed that the genes encoding SHP2-interacting proteins that are critical for ERK activation, such as GAB1 and GRB2, were enriched in excitatory neurons. Accordingly, expressing a dominant-negative mutant of GAB1, which reduced its interaction with SHP2D61G, selectively in excitatory neurons, reversed SHP2D61G-mediated deficits. Moreover, ectopic expression of GAB1 and GRB2 together with SHP2D61G in inhibitory neurons resulted in ERK activation. These results demonstrate that RAS-ERK signaling networks are notably different between excitatory and inhibitory neurons, accounting for the cell type–specific pathophysiology of NS and perhaps other RASopathies.

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